The natural history, prognosis and management of gastrinomas and other malignant pancreatic endocrine tumors (PET's) in patients without (sporadic disease) or with multiple endocrine neoplasia-type 1 (MEN1) is largely based on antedotal reports and small series. Gastrinomas are the most common symptomatic, malignant PET in patients with or without MEN1 and sufficient numbers of these patients have been entered into our protocols to allow systematic assessment. Studies are now underway, evaluating the natural history of these tumors including the presentation and initial diagnosis, definition of factors determining prognosis and improved methods to diagnose these tumors especially in patients with MEN1. Our studies have identified a cohort of 25% of patients in whom the gastrinomas have aggressive growth. Prospective studies assesssing serum gastrin or chromogranin A show they do not predict growth and serial imaging studies are needed. Molecular studies of gastrinomas of patients with or without aggressive tumors demonstrate alterations in the HER2/neu gene, loss of heterozgosity at 1q and overexpression of the EGF and HGF receptors occur in these tumors and their presence correlates with the aggressive growth. Surgical studies completed during the year support a role for aggressive resection in patients with advanced, aggressive disease. Surgical studies also provide strong support that gastrinomas can arise in lymph nodes and therefore they should be aggressively removed at surgery. The possible side-effects of longterm acid secretory control as well as long term hypergastrinemia are being examined including effects on vitamin B-12 and iron absorption as well as the development of gastric carcinoids and methods to identify these. Lastly, prospective studies on patients with ZES and MEN1 demonstrate male patients may develop thymic carcinoids which are extremely aggressive tumors. Their pathogenesis remains unknown because they lack 11q13 LOH which is usually found in most tumors which develop in patients with MEN1.